The proposed experiments will examine the diversity of human class II molecules in relation to their role in disease susceptibility and normal function. Considerable emphasis will be given to experiments directed at clarifying the possibility that Ia molecules have a function in the biology of the human cell independent from an exclusive role in antigen presentation. Attention will be directed to the structure and variation of the intra cellular domain, and the possibility that it undergoes differential interactions with a variety of protein kinases and possibly other molecules. The inhibition of a B-cell proliferative response by certain anti Ia reagents which serves as a model of regulatory control will be studied to account for the divergence in effect of different reagents and to gain insight into the mechanism that is involved. The significance of the polymorphisms of the first domain of the Ia molecules as they may be involved in antigen presentation will also be a major aim of the project. Both germline and possible somatic mutation mechanisms will be explored. The complexity of the serologic and molecular composition of the Ia system will be approached in detail with the view that the epitopes which most likely are involved in the function of the molecule exhibit a complex relationship to conventional serologic specificities.